Cancer accounts for more than a tenth of all mortality worldwide, and according to the World Health Organisation cancer was responsible for 7,600,000 deaths in 2008. In Australia, in 2012 it is estimated that more than 120,700 new cases of cancer will be diagnosed (excluding basal and squamous cell carcinoma of the skin), with the most commonly reported cancers expected to be prostate cancer, followed by bowel cancer, breast cancer, melanoma of the skin and lung cancer. In the United States, more than one million new cancer cases arise each year. Of these, approximately half are classified as early-stage diseases.
As detection technologies improve and strategies for routine screening become widely adopted, the number of early stage cancers with no clear evidence of metastatic spread will increase dramatically. Therefore, the development of new and improved methods for the treatment of cancer is of vital importance. At present, common cancer therapies include the use of chemotherapeutic agents which are delivered systemically and have little or no tumour specificity, which results in the potential for harm to healthy organs in the body and causes symptoms such as myelosuppression, mucositis and alopecia. Various forms of radiation are toxic to mammalian cells and have been harnessed successfully for the treatment of cancer. Radioactive isotopes have been used to treat certain cancers, for example cancers of the thyroid and prostate. However, for logistical reasons including the considerable expense of suitable radiation delivery systems, radiation therapy is used less frequently than would otherwise be desirable. As a result, current cancer treatments are far from ideal.
Malignancies of the skin are the most commonly diagnosed cancer type worldwide. Skin cancers are divided into two types, namely melanoma and non-melanoma, with melanoma being the most serious form. Melanoma originates in melanocytes, and whilst it is not the most common type of skin cancer, it underlies the majority of skin cancer-related deaths. Indeed, each year about 48,000 deaths are registered worldwide as being due to malignant melanoma, with about 160,000 new cases of melanoma diagnosed worldwide annualy.
Melanomas fall into four major categories—Superficial spreading melanoma which travels along the top layer of the skin before penetrating more deeply; Lentigo maligna which typically appears as a flat or mildly elevated mottled tan, brown, or dark brown discoloration, and which is found most often in the elderly; Nodular melanoma which occurs anywhere on the body as a dark, protuberant papule or a plaque that varies from pearl to gray to black; and Acral-lentiginous melanoma which is the most uncommon form of melanoma that arises on palmar, plantar, or subungual skin.
Metastasis of melanoma is common and occurs via lymphatics and blood vessels. Local metastasis results in the formation of nearby satellite papules or nodules that may or may not be pigmented, whilst direct metastasis to skin or internal organs can also occur. Despite many years of intensive laboratory and clinical research, there are still limited treatments for melanoma, and those that are available exhibit resistance and multiple unwanted side effects.
Non-melanoma skin cancer has two major sub-types, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCCs and SCCs of the skin represent the most common malignancies in the Caucasian population (for example a total of 1,300,000 new cases diagnosed in 2000 in the United States alone). Given that SCCs are highly invasive, metastatic, and are associated with a comparatively high risk of recurrence, they result in significant mortality. SCCs can be diagnosed by biopsy; however, SCCs are typically not as distinct as BCCs or melanomas, making detection and diagnosis difficult. Current methods of treatment, including surgery, radiotherapy, and chemotherapy, require continued monitoring due to the metastatic nature of SCCs. The development of alternative methods of detection and treatment are therefore desirable.
The incidence of non-melanoma skin cancers, including metastatic SCC, is increasing due to the aging populations in western society, and because of its enormously increased incidence among organ transplant recipients. For example, the incidence of SCC in transplant recipients is 40 to 250 times that of the general population, whereas the incidence of BCC is 10 times greater in transplant patients. SCCs in transplant patients are much more aggressive and deadly and out of the 5.1% of transplant patients who die from skin cancer, 60% had SCC and 33% had melanoma, which represents a 10-fold increase in mortality from SCC in comparison with the general population.
Colorectal cancer (CRC) originates in either the large intestine (colon) or the rectum. CRC is the third most common cancer in men and the second most common in women worldwide. In 2008, it was estimated that about 608,000 deaths worldwide could be attributed to CRC annually, accounting for 8% of all cancer deaths, and making CRC the fourth most common cause of death from cancer worldwide. CRC arises from the mucosa forming the inner lining of colon and rectum. Like any other mucosa, it needs to be regenerated and proliferates at a high rate (about one third of all fecal matter are mucosa cells), and is thus susceptible to abnormal growth. In fact, abnormal colonic mucosal growth can be detected in about 40% of all persons over the age of 55 years.
Current technologies to detect mucosal neoplasia (polyps/adenoma) and CRC can be categorized into three classes: In vitro diagnostics—a specimen/sample (blood, stool, or urine) is taken from the test person and analyzed for one or more biomarkers as surrogate markers for colorectal neoplasia/cancer. Exemplary tests include the guaic fecal occult blood test (gFOBT) or the immunological fecal occult blood test (iFOBT); Imaging methods without interventional capabilities, such as X-ray, double contrast barium enema (DCBE), video capsule endoscopy, or computed tomographic coionography; and Imaging methods with interventional capabilities, such as flexible sigmoidoscopy, colonoscopy, laparoscopy, or open surgery.
Unfortunately, the clinical utility of a stool-based screen for CRC is limited because individuals are often unwilling to take the test repeatedly due to the nature of the test. Furthermore, the US National Institutes of Health reported that compliance with endoscopy (flexible sigmoidoscopy or colonoscopy) is dependent on the education and income of the population. Colonoscopy is also an invasive procedure, which is not only inconvenient but may be associated with health risks. Therefore, the overall clinical utility of all endoscopy-based CRC screening is also limited. Accordingly, the current clinical utility of a test for detection of CRC depends not only on its performance characteristics, i.e., sensitivity and specificity, but also on acceptance by the patients and the medical community. Alternative therapies would be welcome.
Lung cancer has been one of the most common cancers for several decades and causes the largest number of cancer deaths in the world. In 2008, there were an estimated 1,610,000 newly diagnosed cases in the world (12.7% of the total) with 1,380,000 deaths (18.2% of the total) caused by cancer of the lung. This exceeded the death rates of breast, prostate and colorectal cancer combined. Lung cancer is categorized into two types, namely small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). About 85% of lung cancer cases are categorized as NSCLC, which includes adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma.
The basis for tumor progression and the aggressive biological behavior of lung cancer remains poorly understood. As with other cancers, the survival rate for lung cancer is much higher if it is detected early. However, lung cancer is difficult to diagnose in the early stages because it may manifest no outward symptoms. When symptoms do occur, they can vary depending on the type, location and spreading pattern of the cancer, and therefore, are not readily associated with cancer. Often, lung cancer is only correctly diagnosed when it has already metastasized. When the disease is detected in an early, localized stage and can be removed surgically, the five-year survival rate can reach 85%. But once the cancer has spread to other organs, especially to distant sites, as few as 2% of patients survive five years.
Potential screening tools to detect early stage lung cancer are chest X-ray and computed tomography (CT) scanning. However, the high cost and high rate of false positives render these radiographic tools impractical for routine widespread use. PET scans are another diagnostic option, but PET scans are costly and generally not amenable for use in screening programs. Currently, age and smoking history are the only two risk factors that have been used as selection criteria by the large screening studies. Accordingly, novel lunger cancer detection methods and therapeutic applications are required.
Cancer metastasis involves multiple biological processes driven by an ensemble of genetic alterations. It is understood that either metastasis-conferring genetic events are acquired stochastically as a tumor grows and expands, or that tumors are “hard-wired” with pro-metastatic genetic alterations early in the evolution of tumors and that these alterations also drive the genesis of cancer. Despite a wealth of knowledge at the molecular and genetic level about major cancer forms in humans, including skin, colorectal, lung, breast, liver, pancreas, and other cancers, there is still a very poor understanding of the molecular events underpinning tumor progression and metastasis. Accordingly, there remains a need to understand which patients will have recurrence of their tumors and ultimately a lethal outcome, and how early diagnosis and treatment may impact these outcomes.
In light of the above, there is a need for the identification of new molecular targets responsible for the aetiology, growth and spread of cancer. Such targets may serve as a basis for the therapeutic intervention and diagnosis of cancer.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.